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GRADING OF RECOMMENDATIONS, ASSESSMENT, DEVELOPMENT, AND EVALUATION (GRADE) FOR 

HPV VACCINE FOR MALES 

CDC. Recommendations on the Use of Quadrivalent Human Papillomavirus Vaccine in Males —

Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60:1705-8. 

METHODS FOR GRADE: HPV VACCINE FOR MALES 

Evidence of benefits, harms, values and preferences, and cost-effectiveness were reviewed in 

accordance with GRADE methods. The primary policy question was, “Should HPV4 be recommended for 

routine use in 11-12 year old boys”. The benefits considered included prevention of genital warts, anal 

intraepithelial neoplasia (AIN), and anal cancer. The harms considered included serious adverse events 

(SAE), venous thromboembolism (VTE), syncope, and anaphylaxis. Data on efficacy were from a 

randomized clinical trial of HPV4 in males; data on adverse effects were from randomized clinical trials 

of HPV4 in males and females, and post-licensure studies of HPV4 in females. Evidence type for each 

study included a review of study design, risk of bias, inconsistency, indirectness, imprecision, and other 

considerations.

Recommendation Category A: Recommendation that applies to all persons in an age or risk-based 

group. Recommendation Category B: Recommendation for individual clinical decision making. 

Evidence Type 1: Randomized controlled trials, or overwhelming evidence from observational studies. 

Evidence Type 2: Randomized controlled trials with important limitations, or exceptionally strong 

evidence from observational studies. Evidence Type 3: Observational studies. Evidence Type 4: Clinical 

experience and observations, observational studies, or randomized controlled trials with notable 

limitations. Source: Ahmed F, Temte JL, Campos-Outcalt D, Schünemann HJ; for the ACIP Evidence 

Based Recommendations Work Group (EBRWG). Methods for developing evidence-based 

recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for 

Disease Control and Prevention (CDC). Vaccine 29(49):9171-6, 2011. 

June 13, 2014

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf
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TABLES FOR GRADE: HPV VACCINE FOR MALES

Table 2. Quadrivalent HPV vaccine for Males: Evidence Type of Benefits

Outcome

Design

(# studies) Risk of Bias Inconsistency Indirectness Imprecision

Other 

Considerations

Evidence 

Type

Population: Males

Genital warts RCT (1) No serious No serious No serious No serious None 1

Population: MSM

Genital warts RCT (1) No serious No serious No serious No serious None 1

AIN 1/2/3 RCT (1) No serious No serious No seriousb No serious None 1

AIN2/3 RCT (1) No serious No serious Yesa,b No serious None 2

MSM=men who have sex with men; AIN=anal intraepithelial neoplasia; CI=confidence interval; AIN=anal intraepithelial neoplasia; 

RCT=randomized controlled trial

a

AIN2/3 considered anal precancer lesion (surrogate for anal cancer) downgraded by one level for indirectness; 

b

Evidence in MSM available from 

clinical trial, no reason to suspect vaccine efficacy for boys aged 11-12 years would differ from that observed in MSM, not downgraded for 

indirectness

Table 1. Quadrivalent HPV Vaccine for Males: Benefits*

Outcome

HPV 6-, 11-, 16-, 18-

related

No. subjects 

(# studies)

Incidence in 

controls 

Incidence in 

vaccinated 

Vaccine efficacy 

(95% CI)

Risk difference

per 1000

(95% CI)

Number 

needed to

vaccinated

Population: Malesa

Genital warts 2798

(1 RCT)

1.99% 0.22% 89.3%

(65.3, 97.9)

-18

(-13, -20)

56

Population: MSMb

Genital wartsc402

(1 RCT)

4.33% 0.51% 88.1 

(13.9, 99.7)

-38

(-6, -43)

26

AIN 1/2/3 402

(1 RCT)

11.5% 2.6% 77.5%

(39.6, 93.3) 

-89

(-46, -107)

11 

AIN 2/3 402

(1 RCT)

6.3% 1.5% 74.9%

(8.8, 95.5) 

-48

(-6, -59)

21 

AIN=anal intraepithelial neoplasia; MSM=men who have sex with men; CI=confidence interval; RCT=randomized controlled trial

a

Follow-up 2.3 years; bFollow-up 2.6 years; cPersonal Communication, Carlos Sattler MD, August 2011; dFrequently reported as number needed to treat or NNT 

Reference: from Package insert for Gardasil (quadrivalent human papillomavirus types 6, 11, 16 and 18 HPV); Vaccine efficacy, risk difference, and number 

needed to vaccinate calculated with GRADEpro software *Among those who received all 3 vaccine doses and were seronegative at day 1 and DNA-negative day 

1 through month 7 to the respective HPV type (per protocol population)

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf
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Table 3. Quadrivalent HPV Vaccine for Males: Summary Harms from Prelicensure RCTs in Males and Females

Outcome

No. subjects 

(# studies)

Incidence in vaccinated

%

Incidence in controls

%

Summary risk ratio 

(95% CI)

Malesa

SAE 4723(2 RCTs) 0.4 0.5

0.88 (0.38, 2.06)

Syncope 4723(2 RCTs)

0.04 0.1 0.50 (0.05, 5.52)

VTE 4723(2 RCTs)

0 0 NE

Anaphylaxis 4722(2 RCTs)

0 0 NE

Femalesb

SAE 18,893(4 RCTs) 1.1 1.1 0.97 (0.74, 1.27)

Syncope 18,893(4 RCTs) 0.2 0.2

0.84 (0.45, 1.55)

VTE 18,893(4 RCTs) 0.03 0.02 1.33 (0.30, 5.96)

Anaphylaxis 18,893(4 RCTs) 0 0.01 0.33 (0.01, 8.20)

NE= non estimable; VTE=venous thromboembolism; RCT=randomized controlled trial; CI=confidence interval; SAE=serious adverse events: 

FDA definition including death, hospitalization, life-threatening event, disability, congenital anomaly or birth defect, requiring intervention, or 

other serious event http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm

VTE = deep vein thrombosis, embolism, thrombophlebitis, thrombosis, or thrombophlebitis, superficial; 

a

From Merck protocols 018 (follow-up 2.5 years), 020 (follow-up 3 years) bFrom Merck protocols 007 (follow-up 3 years), 013 (follow-up 3.7 

years), 015 (follow-up 3.7 years), 018 (follow-up 2.5 years). Summary risk ratio calculated using RevMan software, fixed effects 

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf
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Table 4. Quadrivalent HPV Vaccine for Males: Harms from Postlicensure Vaccine Safety Datalink Observational Study in Females

Outcome, age group (yrs)

No. of doses administered

Incidence in vaccinated 

group 

(per 10,000 vaccinations)a

Incidence in comparison 

group 

(per 10,000 vaccinations) Relative risk (95% CI)c

Syncopeb

 9-18 351,630 17.35 21.72 0.86 (0.72, 1.02)

 19-26 150,544 11.29 19.31 0.54 (0.42, 0.75)

VTEb

 9-18 292,302 0.274 0.137 1.98d(0.86,3.94)

 19-26 176,194 0.624 0.851 0.73 (0.37, 1.31)

Anaphylaxise

 9-26 600,558 0.017 0.015 N/A

VTE=venous thromboembolism; CI=confidence interval; N/A=not available

a

For syncope, observed rates presented and risk window was day 0. For VTE, rates were adjusted by site and age. Risk window included days 1-

42; bComparison group for syncope was concurrent vaccinated group; for VTE was historical comparison group;. CRelative Risk adjusted by site 

and age; Simulated confidence intervals at the time upper limit was reached; dConfirmed cases of VTE among 9-17 yr olds all had risk factors for 

VTE (smoking, obesity, oral contraceptive pill use, hypercoaguable disorders); eComparison group from Bolkhe K, et al. Risk of anaphylaxis after 

vaccination of children and adolescents. Pediatrics 2003. Reference: from Gee J, et al. Monitoring the safety of quadrivalent human 

papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf
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Table 5. Quadrivalent HPV Vaccine for Males: Harms from Postlicensure Manufacturer Observational Study in Females

Outcome

No. of 

Persons

Incidence in vaccinated group 

(per 1000 person years)

Incidence in comparison group 

(per 1000 person years) Relative risk (95% CI)a

Syncope 189,629 24.21 4.04 6.00 (3.91,9.21)b

VTE 189,629 6.32 4.97 1.27 (0.57,2.86)

Allergic reaction or 

Anaphylactic Shock

189,629 0.16 0.21 0.75 (0.32,1.78)c

VTE=venous thromboembolism; CI=confidence interval; Outcome is defined as presence of diagnosis code in emergency room or hospital setting in 

vaccination risk period (day of vaccination for syncope & allergic reaction/anaphylactic shock, & 1-60 days after vaccination for VTE) or in postvaccination self-comparison (i.e., “control”) period. These codes could represent a new event, a pre-existing condition, a prior history of the condition, a 

“rule out” diagnosis, miscoding, or a misdiagnosis. A diagnosis code also does not assume that the diagnosis is confirmed. No validation of these codes 

was performed by medical record review. 

a

Relative risk is approximated by odds ratio, obtained from conditional logistic regression;

b

For syncope, the relative risk elevation with lower bound CI 

greater than 1 suggests that syncope diagnosis codes are more likely to occur on day of vaccination than in self-comparison period;

c

For allergic 

reaction/anaphylactic shock, external Safety Review Committee reviewed medical records of females with day 0 diagnosis codes & found no association 

between diagnosis & vaccination with quadrivalent HPV vaccine.

VTE includes the following ICD-9 codes: 452 Portal vein thrombosis; 453.0 Budd-Chiari syndrome; 453.1 Thrombophlebitis migrans; 453.2 Embolism & 

thrombosis of inferior vena cava; 453.3 Embolism & thrombosis of renal vein; 453.4-453.9: Acute and chronic venous embolism & thrombosis of deep or 

superficial vessels or veins at various sites or unspecified site; V12.51 Personal history of venous thrombosis & embolism. Reference: ACIP Presentation 

October 2011 by C. Velicer

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf
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Table 6. Quadrivalent HPV Vaccine for Males: Evidence Type of Harms

Outcome

Design

(# studies, Sex) Risk of bias Inconsistency Indirectness Imprecision

Other 

considerations

Evidence 

type

SAE RCT (2,M: 4,F) No serious No serious No serious aYesb None 2

VTE RCT (2,M; 4,F) No serious No serious No serious aYesb None 2

O (2 F) Yesd No serious Yesc No serious None 4

Syncope RCT (2,M; 4,F) No serious No serious No seriousaYesb None 2

O (2 F) Yesd No serious Yesc No serious None 4

Anaphylaxis RCT (2,M; 4,F) No serious No serious No serious aYesb None 2

O (2 F) Yesd No serious Yesc No serious None 4

VTE=venous thromboembolism; SAE=serious adverse events; RCT=randomized controlled trial; O=observational study

a

Female data indirect, however male data available, not downgraded; bRCTs with relatively small sample size, downgraded one level for 

imprecision;

c

Studies conducted in females, downgraded one level for indirectness;

d

Possible uncontrolled confounding, downgraded one level

for risk of bias

Summary for Harm: No evidence of increased risk for anaphylaxis, VTE, or SAE from 5 RCTs in males and females (1 RCT in both males and 

females), and 2 observational studies in females. One of 7 studies found persons who were vaccinated with HPV4 were more likely to faint on 

the day they were vaccinated than another period in which vaccine was not administered, likely a result of injection-related syncope. 

Injection-related syncope is an anticipated finding that is described in the package insert. In the recommendation for HPV vaccine it is stated 

that syncope can occur after vaccination and to avoid serious injury related to a syncopal episode, vaccine providers should consider observing 

patients for 15 minutes after they are vaccinated. Evidence type is 2 for RCTs and 4 for observational studies.

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf
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Table 7. Summary Evidence Type for Benefits, Harms: Quadrivalent HPV Vaccine for Males

Comparison Group Outcome Study design 

(# studies, sex)

Findings Evidence 

type

Overall 

Evidence type b

HPV vaccination vs. 

no HPV vaccination 

Benefits Genital warts RCT (1,M) Decreased risk among 

vaccinated

1

2

AIN1/2/3 RCT (1,M) Decreased risk among 

vaccinated

1

AIN2/3 RCT (1,M) Decreased risk among 

vaccinated

2

Harms SAE RCT (2, M; 4,F) No difference 2

Syncope RCT (2, M; 4,F) No difference 2

Syncope O (2, F) Increased risk among 

vaccinateda

4

VTE RCT (2, M; 4,F) No difference 2

VTE O (2, F) No difference 4

Anaphylaxis RCT (2, M; 4,F) No difference 2

Anaphylaxis O (2, F) No difference 4

RCT=randomized controlled trial; O=observational study; F=female; M=male; VTE=venous thromboembolism; SAE=serious adverse events 

aOne observational study found persons who were vaccinated with HPV4 were more likely to faint on the day they were vaccinated than 

another period in which vaccine was not administered bOverall evidence type 2 based on evidence from the strongest study design for critical 

harms and benefits

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf
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Table 8. Considerations for Formulating Recommendations: Quadrivalent HPV Vaccine for Males

Key factors Comments

Balance between benefits and 

harms

Benefits are greater than potential harms 

Evidence type for benefits and 

harms

Evidence Type 2 Benefit 

Evidence Type 2 Harm RCT 

Evidence Type 4 Harm O

Value High value placed by ACIP HPV Work Group on prevention of cancer in males 

Cost-effectiveness HPV4 is most cost-effective if all HPV associated outcomes prevented, vaccine cost lower than current price, 

female coverage low (such as 30% 3-dose coverage at age 12 years)

RCT=randomized controlled trial; O=observational study

Summary for Benefits and Harms: Benefits are greater than potential harms and overall evidence type is 2. There is high value placed on 

prevention of cancer in males. Quadrivalent HPV vaccine is most cost-effective if all HPV associated outcomes are prevented, vaccine cost is 

lower than current price, or female coverage is low. Recommendation for routine vaccination of males aged 11 or 12 years with HPV4 

administered as a 3-dose series (recommendation category A; evidence type 2)

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf
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References:

1. C Velicer. ACIP Presentation. Post-licensure Safety Study of Quadrivalent Human Papillomavirus 

Vaccine among 189,629 Females Presented at October 2011 ACIP Meeting. 

2. Ahmed F, Temte JL, Campos-Outcalt D, Schünemann HJ, for the ACIP Evidence Based 

Recommendations Work Group (EBRWG). Methods for developing evidence-based 

recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers 

for Disease Control and Prevention (CDC). Vaccine 2011;29:9171-76.

3. Bohlke K, Davis RL, DeStefano F, Marcy SM, Braun MM, Thompson RS; Vaccine Safety Datalink Team. 

Epidemiology of anaphylaxis among children and adolescents enrolled in a health maintenance 

organization. J Allergy Clin Immunol 2004;113:536-42.

4. Chesson HW, Ekwueme DU, Saraiya M, Dunne EF, Markowitz LE. The cost-effectiveness of male HPV 

vaccination in the United States. Vaccine 2011;29:8443-50.

5. Food and Drug Administration, Product approval information – licensing action, package insert: 

Gardasil (quadrivalent human papillomavirus types 6, 11, 16 and 18 HPV), Merck & Co. Whitehouse 

Station, NJ: Food and Drug Administration; 2009. 

6. Gee J, Naleway A, Shui I,et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: 

findings from the Vaccine Safety Datalink. Vaccine 2011;29:8279-84. 

7. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV 

infection and disease in males. N Engl J Med 2011;364:401-11. 

8. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal 

intraepithelial neoplasia. N Engl J Med 2011;365:1576-85.

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.pdf